Project Summary Most diseases occur differently in males and females, indicating that one sex is protected by factors that are inherently different in the two sexes. Understanding the mechanisms of protection involves isolating different molecular pathways causing greater or less protection. Sex chromosomes (XX vs. XY) are one major source of sex bias within any type of cell, but this category has been difficult to discriminate from gonadal hormone effects that often co-vary with sex chromosome complement. To isolate and study sex chromosome effects, it is necessary to make experimental models with XX and XY animals with the same type of gonad. No such models exist in rats. Rats are superior models for many diseases and physiological processes. The proposal is to genetically modify rats to produce XX and XY rats with testes, and XX and XY rats with ovaries, to be studied in many different rat models of disease, relevant to nearly any NIH institute. The testis- determining gene Sry, present on the Y chromosome, will be inserted as a transgene onto an autosome, so that XX(Sry-tg+) gonadal male rats can be compared with XY gonadal male rats. Then, Sry will be knocked out from the Y chromosome, producing XY rats with ovaries, gonadal females, which can be compared with XX gonadal females to detect the differential effects of XX vs. XY sex chromosomes. The basic gonadal and body development of these rats will be studied to validate their use in numerous rat models of disease, including brain and behavioral phenotypes, cardiovascular and pulmonary diseases, etc. The successful models will be deposited in the Rat Resources & Research Center and made widely available to other investigators.